Our goal is to define the mechanisms by which cell surface molecules function in T cell recognition of foreign cell surface antigens. Studies of the functional roles of the T cell surface molecules T3, T4, and LFA-1 demonstrated that there was an inverse correlation beween the avidity of individual T4+ CTL clones for their specific targets and their susceptibility to inhibition by anti-T3 and anti-T4, but not anti-LFA-1, monoclonal antibodies. The quantity and interaction of cell surface antigen-specific T cell receptor (Ti) molecules and the T3 complex were examined on those CTL clones that are of the highest avidity and most resistant to blocking by anti-T3 antibodies to examine the hypothesis that the Ti molecules on these clones were not strongly physically associated with the T3 complex. No significant differences were found between highly resistant and susceptible clones for: 1) the levels of cell surface expression of the T3 complex and Ti; 2) the ability to modulate T3 cell surface molecules; and 3) the capacity of the Ti molecules to co-modulate with the T3 complex. The most likely explanation for the observed heterogeneity in susceptibility to blocking by anti-T3 antibodies is, therefore, thought to be that individual CTL clones possess Ti molecules with differential avidity for specific targets. The dissection of the molecular basis for T cell recognition of class I HLA antigens has been continued with the use of cloned HLA-A3 genes transfected into mouse cells by DNA-mediated gene transfer. HLA-A3-specific allo-reactive CTL and HLA-A3-restricted influenza virus-specific human CTL have been shown to be able to specifically lyse the appropriate mouse cell transfectants. These results demonstrate that the only human gene product required on target cells for recognition by allo-reactive and HLA-restricted class I CTL is the HLA heavy chain.